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B cells in systemic sclerosis: from pathophysiology to treatment

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Abstract

Systemic sclerosis is a debilitating autoimmune disease with unknown pathogenesis. The clinical phenotype of fibrosis is preceded by vascular and immunologic aberrations. Adaptive immunity has been extensively studied in patients with the disease and B cells appear to be dysregulated. This is evident in peripheral blood B cell subsets, with activated effector B cells and impaired B regulatory function. In addition, B cells infiltrate target organs and tissues of patients with the disease, such as the skin and the lung, indicating a probable role in the pathogenesis. Impaired B cell homeostasis explains the rationale behind B cell therapeutic targeting. Indeed, several studies in recent years have shown that depletion of B cells appears to be a promising treatment alongside current established therapeutic choices, such as mycophenolate. In this review, B cell aberrations in animal models and human patients with systemic sclerosis will be presented. Moreover, we will also summarize current existing data regarding therapeutic targeting of the B cells in systemic sclerosis.

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References

  1. Elhai M, Meune C, Avouac J, Kahan A, Allanore Y (2012) Trends in mortality in patients with systemic sclerosis over 40 years: a systematic review and meta-analysis of cohort studies. Rheumatology 51:1017–1026. https://doi.org/10.1093/rheumatology/ker269

    Article  PubMed  Google Scholar 

  2. Gabrielli A, Avvedimento EV, Krieg T (2009) Scleroderma. N Engl J Med 360:1989–2003. https://doi.org/10.1056/NEJMra0806188

    Article  CAS  PubMed  Google Scholar 

  3. Denton CP, Khanna D (2017) Systemic sclerosis. Lancet 390:1685–1699. https://doi.org/10.1016/S0140-6736(17)30933-9

    Article  PubMed  Google Scholar 

  4. Brown M, O’Reilly S (2018) The immunopathogenesis of fibrosis in systemic sclerosis. Clin Exp Immunol. https://doi.org/10.1111/cei.13238

  5. van den Hoogen F, Khanna D, Fransen J, Johnson SR, Baron M, Tyndall A, Matucci-Cerinic M, Naden RP, Medsger TA Jr, Carreira PE, Riemekasten G, Clements PJ, Denton CP, Distler O, Allanore Y, Furst DE, Gabrielli A, Mayes MD, van Laar JM, Seibold JR, Czirjak L, Steen VD, Inanc M, Kowal-Bielecka O, Müller-Ladner U, Valentini G, Veale DJ, Vonk MC, Walker UA, Chung L, Collier DH, Csuka ME, Fessler BJ, Guiducci S, Herrick A, Hsu VM, Jimenez S, Kahaleh B, Merkel PA, Sierakowski S, Silver RM, Simms RW, Varga J, Pope JE (2013) 2013 Classification criteria for systemic sclerosis: an American College of Rheumatology/European League Against Rheumatism Collaborative Initiative: ACR/EULAR Classification Criteria for SSc. Arthritis Rheum 65:2737–2747. https://doi.org/10.1002/art.38098

    Article  PubMed  PubMed Central  Google Scholar 

  6. Mehra S, Walker J, Patterson K, Fritzler MJ (2013) Autoantibodies in systemic sclerosis. Autoimmun Rev 12:340–354. https://doi.org/10.1016/j.autrev.2012.05.011

    Article  CAS  PubMed  Google Scholar 

  7. Sakkas LI, Xu B, Artlett CM, Lu S, Jimenez SA, Platsoucas CD (2002) Oligoclonal T cell expansion in the skin of patients with systemic sclerosis. J Immunol 168:3649–3659. https://doi.org/10.4049/jimmunol.168.7.3649

    Article  CAS  PubMed  Google Scholar 

  8. Eibel H, Kraus H, Sic H, Kienzler AK, Rizzi M (2014) B cell biology: an overview. Curr Allergy Asthma Rep 14:434. https://doi.org/10.1007/s11882-014-0434-8

    Article  CAS  PubMed  Google Scholar 

  9. Baumgarth N (2011) The double life of a B-1 cell: self-reactivity selects for protective effector functions. Nat Rev Immunol 11:34–46. https://doi.org/10.1038/nri2901

    Article  CAS  PubMed  Google Scholar 

  10. Allman D, Pillai S (2008) Peripheral B cell subsets. Curr Opin Immunol 20:149–157. https://doi.org/10.1016/j.coi.2008.03.014

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  11. Rosser EC, Mauri C (2015) Regulatory B cells: origin, phenotype, and function. Immunity 42:607–612. https://doi.org/10.1016/j.immuni.2015.04.005

    Article  CAS  PubMed  Google Scholar 

  12. Dalporto J (2004) B cell antigen receptor signaling 101. Mol Immunol 41:599–613. https://doi.org/10.1016/j.molimm.2004.04.008

    Article  CAS  Google Scholar 

  13. Harwood NE, Batista FD (2008) New insights into the early molecular events underlying B cell activation. Immunity 28:609–619. https://doi.org/10.1016/j.immuni.2008.04.007

    Article  CAS  PubMed  Google Scholar 

  14. Kurosaki T (2011) Regulation of BCR signaling. Mol Immunol 48:1287–1291. https://doi.org/10.1016/j.molimm.2010.12.007

    Article  CAS  PubMed  Google Scholar 

  15. Tedder TF, Sato S, Poe JC, Fujimoto M (2000) CD19 and CD22 regulate a B lymphocyte signal transduction pathway that contributes to autoimmunity. Keio J Med 49:1–13. https://doi.org/10.2302/kjm.49.1

    Article  CAS  PubMed  Google Scholar 

  16. Doody GM, Dempsey PW, Fearon DT (1996) Activation of B lymphocytes: integrating signals from CD19, CD22 and FcγRIIb1. Curr Opin Immunol 8:378–382. https://doi.org/10.1016/S0952-7915(96)80128-2

    Article  CAS  PubMed  Google Scholar 

  17. Whitmire JK, Asano MS, Kaech SM, Sarkar S, Hannum LG, Shlomchik MJ, Ahmed R (2009) Requirement of B cells for generating CD4+ T cell memory. J Immunol 182:1868–1876. https://doi.org/10.4049/jimmunol.0802501

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  18. Mackay F, Schneider P, Rennert P, Browning J (2003) BAFF and APRIL: a tutorial on B cell survival. Annu Rev Immunol 21:231–264. https://doi.org/10.1146/annurev.immunol.21.120601.141152

    Article  CAS  PubMed  Google Scholar 

  19. Wardemann H, Yurasov S, Schaefer A et al (2003) Predominant autoantibody production by early human B cell precursors. Sci New Ser 301:1374–1377

    CAS  Google Scholar 

  20. Pillai S, Mattoo H, Cariappa A (2011) B cells and autoimmunity. Curr Opin Immunol 23:721–731. https://doi.org/10.1016/j.coi.2011.10.007

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  21. Platt JL, Garcia de Mattos Barbosa M, Cascalho M (2019) The five dimensions of B cell tolerance. Immunol Rev 292:180–193. https://doi.org/10.1111/imr.12813

    Article  CAS  PubMed  Google Scholar 

  22. Asano Y, Sato S (2013) Animal models of scleroderma: current state and recent development. Curr Rheumatol Rep 15. https://doi.org/10.1007/s11926-013-0382-7

  23. Marangoni RG, Varga J, Tourtellotte WG (2016) Animal models of scleroderma: recent progress. Curr Opin Rheumatol 28:561–570. https://doi.org/10.1097/BOR.0000000000000331

    Article  CAS  PubMed  Google Scholar 

  24. Maurer B, Distler JHW, Distler O (2013) The Fra-2 transgenic mouse model of systemic sclerosis. Vasc Pharmacol 58:194–201. https://doi.org/10.1016/j.vph.2012.12.001

    Article  CAS  Google Scholar 

  25. Saito S, Kasturi K, Bona C (1999) Genetic and immunologic features associated with scleroderma-like syndrome of TSK mice. Curr Rheumatol Rep 1:34–37

    Article  CAS  Google Scholar 

  26. Long KB, Artlett CM, Blankenhorn EP (2014) Tight skin 2 mice exhibit a novel time line of events leading to increased extracellular matrix deposition and dermal fibrosis. Matrix Biol 38:91–100. https://doi.org/10.1016/j.matbio.2014.05.002

    Article  CAS  PubMed  Google Scholar 

  27. Phelps RG, Daian C, Shibata S, Fleischmajer R, Bona CA (1993) Induction of skin fibrosis and autoantibodies by infusion of immunocompetent cells from tight skin mice into C57BL/6 Pa/Pa mice. J Autoimmun 6:701–718. https://doi.org/10.1006/jaut.1993.1059

    Article  CAS  PubMed  Google Scholar 

  28. Sato S, Hasegawa M, Fujimoto M et al (2000) Quantitative genetic variation in CD19 expression correlates with autoimmunity. J Immunol 165:6635–6643. https://doi.org/10.4049/jimmunol.165.11.6635

    Article  CAS  PubMed  Google Scholar 

  29. Saito E, Fujimoto M, Hasegawa M et al (2002) CD19-Dependent B lymphocyte signaling thresholds influence skin fibrosis and autoimmunity in the tight-skin mouse. J Clin Invest 109:1453–1462. https://doi.org/10.1172/JCI200215078

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  30. Asano N, Fujimoto M, Yazawa N, Shirasawa S, Hasegawa M, Okochi H, Tamaki K, Tedder TF, Sato S (2004) B lymphocyte signaling established by the CD19/CD22 loop regulates autoimmunity in the tight-skin mouse. Am J Pathol 165:641–650. https://doi.org/10.1016/S0002-9440(10)63328-7

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  31. Odaka M, Hasegawa M, Hamaguchi Y et al (2010) Autoantibody-mediated regulation of B cell responses by functional anti-CD22 autoantibodies in patients with systemic sclerosis. Clin Exp Immunol 159:176–184. https://doi.org/10.1111/j.1365-2249.2009.04059.x

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  32. Hasegawa M, Hamaguchi Y, Yanaba K, Bouaziz JD, Uchida J, Fujimoto M, Matsushita T, Matsushita Y, Horikawa M, Komura K, Takehara K, Sato S, Tedder TF (2006) B-Lymphocyte depletion reduces skin fibrosis and autoimmunity in the tight-skin mouse model for systemic sclerosis. Am J Pathol 169:954–966. https://doi.org/10.2353/ajpath.2006.060205

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  33. Matsushita T, Fujimoto M, Hasegawa M, Matsushita Y, Komura K, Ogawa F, Watanabe R, Takehara K, Sato S (2007) BAFF antagonist attenuates the development of skin fibrosis in tight-skin mice. J Invest Dermatol 127:2772–2780. https://doi.org/10.1038/sj.jid.5700919

    Article  CAS  PubMed  Google Scholar 

  34. Yamamoto T, Takagawa S, Katayama I, Yamazaki K, Hamazaki Y, Shinkai H, Nishioka K (1999) Animal model of sclerotic skin. I: local injections of bleomycin induce sclerotic skin mimicking scleroderma. J Invest Dermatol 112:456–462. https://doi.org/10.1046/j.1523-1747.1999.00528.x

    Article  CAS  PubMed  Google Scholar 

  35. Yoshizaki A, Iwata Y, Komura K, Ogawa F, Hara T, Muroi E, Takenaka M, Shimizu K, Hasegawa M, Fujimoto M, Tedder TF, Sato S (2008) CD19 regulates skin and lung fibrosis via Toll-like receptor signaling in a model of bleomycin-induced scleroderma. Am J Pathol 172:1650–1663. https://doi.org/10.2353/ajpath.2008.071049

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  36. Komura K, Yanaba K, Horikawa M, Ogawa F, Fujimoto M, Tedder TF, Sato S (2008) CD19 regulates the development of bleomycin-induced pulmonary fibrosis in a mouse model. Arthritis Rheum 58:3574–3584. https://doi.org/10.1002/art.23995

    Article  CAS  PubMed  Google Scholar 

  37. Matsushita T, Kobayashi T, Mizumaki K et al (2018) BAFF inhibition attenuates fibrosis in scleroderma by modulating the regulatory and effector B cell balance. Sci Adv 4:eaas9944. https://doi.org/10.1126/sciadv.aas9944

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  38. Sanges S, Jendoubi M, Kavian N, Hauspie C, Speca S, Crave JC, Guerrier T, Lefèvre G, Sobanski V, Savina A, Hachulla E, Hatron PY, Labalette M, Batteux F, Dubucquoi S, Launay D (2017) B cell homeostasis and functional properties are altered in an hypochlorous acid-induced murine model of systemic sclerosis. Front Immunol 8:8. https://doi.org/10.3389/fimmu.2017.00053

    Article  CAS  Google Scholar 

  39. Zhao C, Matsushita T, Ha Nguyen VT, Tennichi M, Fujimoto M, Takehara K, Hamaguchi Y (2020) CD22 and CD72 contribute to the development of scleroderma in a murine model. J Dermatol Sci 97:66–76. https://doi.org/10.1016/j.jdermsci.2019.12.007

    Article  CAS  PubMed  Google Scholar 

  40. Sato S, Fujimoto M, Hasegawa M, Takehara K (2004) Altered blood B lymphocyte homeostasis in systemic sclerosis: expanded naive B cells and diminished but activated memory B cells. Arthritis Rheum 50:1918–1927. https://doi.org/10.1002/art.20274

    Article  PubMed  Google Scholar 

  41. Soto L, Ferrier A, Aravena O et al (2015) Systemic sclerosis patients present alterations in the expression of molecules involved in B-cell regulation. Front Immunol. https://doi.org/10.3389/fimmu.2015.00496

  42. Mavropoulos A, Simopoulou T, Varna A, Liaskos C, Katsiari CG, Bogdanos DP, Sakkas LI (2016) Breg cells are numerically decreased and functionally impaired in patients with systemic sclerosis: BREG CELLS IN SYSTEMIC SCLEROSIS. Arthritis Rheum 68:494–504. https://doi.org/10.1002/art.39437

    Article  CAS  Google Scholar 

  43. Forestier A, Guerrier T, Jouvray M, Giovannelli J, Lefèvre G, Sobanski V, Hauspie C, Hachulla E, Hatron PY, Zéphir H, Vermersch P, Labalette M, Launay D, Dubucquoi S (2018) Altered B lymphocyte homeostasis and functions in systemic sclerosis. Autoimmun Rev 17:244–255. https://doi.org/10.1016/j.autrev.2017.10.015

    Article  CAS  PubMed  Google Scholar 

  44. Taher TE, Ong VH, Bystrom J, Hillion S, Simon Q, Denton CP, Pers JO, Abraham DJ, Mageed RA (2018) Association of defective regulation of autoreactive interleukin-6-producing transitional B lymphocytes with disease in patients with systemic sclerosis. Arthritis Rheum 70:450–461. https://doi.org/10.1002/art.40390

    Article  CAS  Google Scholar 

  45. Matsushita T, Hamaguchi Y, Hasegawa M, Takehara K, Fujimoto M (2016) Decreased levels of regulatory B cells in patients with systemic sclerosis: association with autoantibody production and disease activity. Rheumatology 55:263–267. https://doi.org/10.1093/rheumatology/kev331

    Article  CAS  PubMed  Google Scholar 

  46. Dumoitier N, Chaigne B, Régent A, Lofek S, Mhibik M, Dorfmüller P, Terrier B, London J, Bérezné A, Tamas N, Varin-Blank N, Mouthon L (2017) Scleroderma peripheral B lymphocytes secrete interleukin-6 and transforming growth factor β and activate fibroblasts. Arthritis Rheum 69:1078–1089. https://doi.org/10.1002/art.40016

    Article  CAS  Google Scholar 

  47. Matsushita T, Hasegawa M, Yanaba K, Kodera M, Takehara K, Sato S (2006) Elevated serum BAFF levels in patients with systemic sclerosis: enhanced BAFF signaling in systemic sclerosis B lymphocytes. Arthritis Rheum 54:192–201. https://doi.org/10.1002/art.21526

    Article  CAS  PubMed  Google Scholar 

  48. Matsushita T, Fujimoto M, Hasegawa M, Tanaka C, Kumada S, Ogawa F, Takehara K, Sato S (2007) Elevated serum APRIL levels in patients with systemic sclerosis: distinct profiles of systemic sclerosis categorized by APRIL and BAFF. J Rheumatol 34:2056–2062

    CAS  PubMed  Google Scholar 

  49. Bielecki M, Kowal K, Lapinska A et al (2010) Increased production of a proliferation-inducing ligand (APRIL) by peripheral blood mononuclear cells is associated with antitopoisomerase I antibody and more severe disease in systemic sclerosis. J Rheumatol 37:2286–2289. https://doi.org/10.3899/jrheum.100454

    Article  PubMed  Google Scholar 

  50. Melissaropoulos K, Liossis S-N (2018) Decreased CD22 expression and intracellular signaling aberrations in B cells of patients with systemic sclerosis. Rheumatol Int 38:1225–1234. https://doi.org/10.1007/s00296-018-4076-3

    Article  CAS  PubMed  Google Scholar 

  51. Tsuchiya N, Kuroki K, Fujimoto M, Murakami Y, Tedder TF, Tokunaga K, Takehara K, Sato S (2004) Association of a functionalCD19 polymorphism with susceptibility to systemic sclerosis. Arthritis Rheum 50:4002–4007. https://doi.org/10.1002/art.20674

    Article  CAS  PubMed  Google Scholar 

  52. Hitomi Y, Tsuchiya N, Hasegawa M et al (2007) Association of CD22 gene polymorphism with susceptibility to limited cutaneous systemic sclerosis. Tissue Antigens 69:242–249. https://doi.org/10.1111/j.1399-0039.2007.00801.x

    Article  CAS  PubMed  Google Scholar 

  53. Yagi-Numata N, Matsushita T, Takehara K, Hamaguchi Y (2019) Increased expression levels of FcγRIIB on naïve and double- negative memory B cells in patients with systemic sclerosis. Clin Exp Rheumatol 37 Suppl 119:23–31

  54. Lafyatis R, O’Hara C, Feghali-Bostwick CA, Matteson E (2007) B cell infiltration in systemic sclerosis–associated interstitial lung disease. Arthritis Rheum 56:3167–3168. https://doi.org/10.1002/art.22847

    Article  PubMed  Google Scholar 

  55. De Santis M, Bosello SL, Peluso G et al (2012) Bronchoalveolar lavage fluid and progression of scleroderma interstitial lung disease: scleroderma interstitial lung disease. Clin Respir J 6:9–17. https://doi.org/10.1111/j.1752-699X.2010.00228.x

    Article  PubMed  Google Scholar 

  56. Fleischmajer R, Perlish JS, Reeves JRT (1977) Cellular infiltrates in scleroderma skin. Arthritis Rheum 20:975–984. https://doi.org/10.1002/art.1780200410

    Article  CAS  PubMed  Google Scholar 

  57. Roumm AD, Whiteside TL, Medsger TA, Rodnan GP (1984) Lymphocytes in the skin of patients with progressive systemic sclerosis. Arthritis Rheum 27:645–653. https://doi.org/10.1002/art.1780270607

    Article  CAS  PubMed  Google Scholar 

  58. Whitfield ML, Finlay DR, Murray JI, Troyanskaya OG, Chi JT, Pergamenschikov A, McCalmont TH, Brown PO, Botstein D, Connolly MK (2003) Systemic and cell type-specific gene expression patterns in scleroderma skin. Proc Natl Acad Sci 100:12319–12324. https://doi.org/10.1073/pnas.1635114100

    Article  CAS  PubMed  Google Scholar 

  59. Milano A, Pendergrass SA, Sargent JL, George LK, McCalmont TH, Connolly MK, Whitfield ML (2008) Molecular subsets in the gene expression signatures of scleroderma skin. PLoS ONE 3:e2696. https://doi.org/10.1371/journal.pone.0002696

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  60. Skaug B, Khanna D, Swindell WR, Hinchcliff ME, Frech TM, Steen VD, Hant FN, Gordon JK, Shah AA, Zhu L, Zheng WJ, Browning JL, Barron AMS, Wu M, Visvanathan S, Baum P, Franks JM, Whitfield ML, Shanmugam VK, Domsic RT, Castelino FV, Bernstein EJ, Wareing N, Lyons MA, Ying J, Charles J, Mayes MD, Assassi S (2020) Global skin gene expression analysis of early diffuse cutaneous systemic sclerosis shows a prominent innate and adaptive inflammatory profile. Ann Rheum Dis 79:379–386. https://doi.org/10.1136/annrheumdis-2019-215894

    Article  CAS  PubMed  Google Scholar 

  61. Bosello S, Angelucci C, Lama G, Alivernini S, Proietti G, Tolusso B, Sica G, Gremese E, Ferraccioli G (2018) Characterization of inflammatory cell infiltrate of scleroderma skin: B cells and skin score progression. Arthritis Res Ther 20:75. https://doi.org/10.1186/s13075-018-1569-0

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  62. Usategui A, del Rey MJ, Pablos JL (2011) Fibroblast abnormalities in the pathogenesis of systemic sclerosis. Expert Rev Clin Immunol 7:491–498. https://doi.org/10.1586/eci.11.39

    Article  CAS  PubMed  Google Scholar 

  63. Worrell JC, O’Reilly S (2020) Bi-directional communication: conversations between fibroblasts and immune cells in systemic sclerosis. J Autoimmun 113:102526. https://doi.org/10.1016/j.jaut.2020.102526

    Article  CAS  PubMed  Google Scholar 

  64. Daoussis D, Liossis S-NC (2013) B cells tell scleroderma fibroblasts to produce collagen. Arthritis Res Ther 15:125. https://doi.org/10.1186/ar4392

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  65. Terrier B, Tamby MC, Camoin L, Guilpain P, Bérezné A, Tamas N, Broussard C, Hotellier F, Humbert M, Simonneau G, Guillevin L, Mouthon L (2010) Antifibroblast antibodies from systemic sclerosis patients bind to α-enolase and are associated with interstitial lung disease. Ann Rheum Dis 69:428–433. https://doi.org/10.1136/ard.2008.104299

    Article  CAS  PubMed  Google Scholar 

  66. Hénault J, Tremblay M, Clément I, Raymond Y, Senécal JL (2004) Direct binding of anti-DNA topoisomerase I autoantibodies to the cell surface of fibroblasts in patients with systemic sclerosis: antifibroblast autoantibodies in SSc. Arthritis Rheum 50:3265–3274. https://doi.org/10.1002/art.20515

    Article  CAS  PubMed  Google Scholar 

  67. Fineschi S, Goffin L, Rezzonico R, Cozzi F, Dayer JM, Meroni PL, Chizzolini C (2008) Antifibroblast antibodies in systemic sclerosis induce fibroblasts to produce profibrotic chemokines, with partial exploitation of toll-like receptor 4. Arthritis Rheum 58:3913–3923. https://doi.org/10.1002/art.24049

    Article  CAS  PubMed  Google Scholar 

  68. Baroni SS, Luchetti M, Fraticelli P et al (2006) Stimulatory autoantibodies to the PDGF receptor in systemic sclerosis. N Engl J Med 10

  69. Loizos N, LaRiccia L, Weiner J et al (2009) Lack of detection of agonist activity by antibodies to platelet-derived growth factor receptor α in a subset of normal and systemic sclerosis patient sera. Arthritis Rheum 60:1145–1151. https://doi.org/10.1002/art.24365

    Article  CAS  PubMed  Google Scholar 

  70. Classen J-F, Henrohn D, Rorsman F, Lennartsson J, Lauwerys BR, Wikström G, Rorsman C, Lenglez S, Franck-Larsson K, Tomasi JP, Kämpe O, Vanthuyne M, Houssiau FA, Demoulin JB (2009) Lack of evidence of stimulatory autoantibodies to platelet-derived growth factor receptor in patients with systemic sclerosis. Arthritis Rheum 60:1137–1144. https://doi.org/10.1002/art.24381

    Article  CAS  PubMed  Google Scholar 

  71. Sato S, Hayakawa I, Hasegawa M, Takehara K, Fujimoto M (2003) Function blocking autoantibodies against matrix metalloproteinase-1 in patients with systemic sclerosis. J Invest Dermatol 120:542–547. https://doi.org/10.1046/j.1523-1747.2003.12097.x

    Article  CAS  PubMed  Google Scholar 

  72. Zhou X, Tan FK, Milewicz DM, Guo X, Bona CA, Arnett FC (2005) Autoantibodies to fibrillin-1 activate normal human fibroblasts in culture through the TGF-pathway to recapitulate the “scleroderma phenotype”. J Immunol 175:4555–4560. https://doi.org/10.4049/jimmunol.175.7.4555

    Article  CAS  PubMed  Google Scholar 

  73. Sato S, Hasegawa M, Takehara K (2001) Serum levels of interleukin-6 and interleukin-10 correlate with total skin thickness score in patients with systemic sclerosis. J Dermatol Sci 27:140–146. https://doi.org/10.1016/S0923-1811(01)00128-1

    Article  CAS  PubMed  Google Scholar 

  74. François A, Chatelus E, Wachsmann D, Sibilia J, Bahram S, Alsaleh G, Gottenberg JE (2013) B lymphocytes and B-cell activating factor promote collagen and profibrotic markers expression by dermal fibroblasts in systemic sclerosis. Arthritis Res Ther 15:R168. https://doi.org/10.1186/ar4352

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  75. Tashkin DP, Elashoff R, Clements PJ, Goldin J, Roth MD, Furst DE, Arriola E, Silver R, Strange C, Bolster M, Seibold JR, Riley DJ, Hsu VM, Varga J, Schraufnagel DE, Theodore A, Simms R, Wise R, Wigley F, White B, Steen V, Read C, Mayes M, Parsley E, Mubarak K, Connolly MK, Golden J, Olman M, Fessler B, Rothfield N, Metersky M (2006) Cyclophosphamide versus placebo in scleroderma lung disease. N Engl J Med 354:2655–2666. https://doi.org/10.1056/NEJMoa055120

    Article  CAS  PubMed  Google Scholar 

  76. Tashkin DP, Roth MD, Clements PJ, Furst DE, Khanna D, Kleerup EC, Goldin J, Arriola E, Volkmann ER, Kafaja S, Silver R, Steen V, Strange C, Wise R, Wigley F, Mayes M, Riley DJ, Hussain S, Assassi S, Hsu VM, Patel B, Phillips K, Martinez F, Golden J, Connolly MK, Varga J, Dematte J, Hinchcliff ME, Fischer A, Swigris J, Meehan R, Theodore A, Simms R, Volkov S, Schraufnagel DE, Scholand MB, Frech T, Molitor JA, Highland K, Read CA, Fritzler MJ, Kim GHJ, Tseng CH, Elashoff RM, Sclerodema Lung Study II Investigators (2016) Mycophenolate mofetil versus oral cyclophosphamide in scleroderma-related interstitial lung disease (SLS II): a randomised controlled, double-blind, parallel group trial. Lancet Respir Med 4:708–719. https://doi.org/10.1016/S2213-2600(16)30152-7

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  77. Van Laar JM, Sullivan K (2013) Stem cell transplantation in systemic sclerosis. Curr Opin Rheumatol 25:719–725. https://doi.org/10.1097/01.bor.0000434669.32150.ac

    Article  CAS  PubMed  Google Scholar 

  78. Sullivan KM, Goldmuntz EA, Keyes-Elstein L, McSweeney PA, Pinckney A, Welch B, Mayes MD, Nash RA, Crofford LJ, Eggleston B, Castina S, Griffith LM, Goldstein JS, Wallace D, Craciunescu O, Khanna D, Folz RJ, Goldin J, St. Clair EW, Seibold JR, Phillips K, Mineishi S, Simms RW, Ballen K, Wener MH, Georges GE, Heimfeld S, Hosing C, Forman S, Kafaja S, Silver RM, Griffing L, Storek J, LeClercq S, Brasington R, Csuka ME, Bredeson C, Keever-Taylor C, Domsic RT, Kahaleh MB, Medsger T, Furst DE (2018) Myeloablative autologous stem-cell transplantation for severe scleroderma. N Engl J Med 378:35–47

    Article  Google Scholar 

  79. Gernert M, Tony H-P, Schwaneck EC, Gadeholt O, Schmalzing M (2019) Autologous hematopoietic stem cell transplantation in systemic sclerosis induces long-lasting changes in B cell homeostasis toward an anti-inflammatory B cell cytokine pattern. Arthritis Res Ther 21:106. https://doi.org/10.1186/s13075-019-1889-8

    Article  PubMed  PubMed Central  Google Scholar 

  80. Misra DP, Ahmed S, Agarwal V (2020) Is biological therapy in systemic sclerosis the answer? Rheumatol Int 40:679–694. https://doi.org/10.1007/s00296-020-04515-6

    Article  PubMed  Google Scholar 

  81. Bellan M, Patrucco F, Barone-Adesi F, Gavelli F, Castello LM, Nerviani A, Andreoli L, Cavagna L, Pirisi M, Sainaghi PP (2020) Targeting CD20 in the treatment of interstitial lung diseases related to connective tissue diseases: a systematic review. Autoimmun Rev 19:102453. https://doi.org/10.1016/j.autrev.2019.102453

    Article  CAS  PubMed  Google Scholar 

  82. Daoussis D, Liossis S-NC, Tsamandas AC et al (2010) Experience with rituximab in scleroderma: results from a 1-year, proof-of-principle study. Rheumatology 49:271–280. https://doi.org/10.1093/rheumatology/kep093

    Article  CAS  PubMed  Google Scholar 

  83. Sircar G, Goswami RP, Sircar D, Ghosh A, Ghosh P (2018) Intravenous cyclophosphamide vs rituximab for the treatment of early diffuse scleroderma lung disease: open label, randomized, controlled trial. Rheumatology 57:2106–2113. https://doi.org/10.1093/rheumatology/key213

    Article  CAS  PubMed  Google Scholar 

  84. Boonstra M, Meijs J, Dorjée AL, Marsan NA, Schouffoer A, Ninaber MK, Quint KD, Bonte-Mineur F, Huizinga TWJ, Scherer HU, de Vries-Bouwstra JK (2017) Rituximab in early systemic sclerosis. RMD Open 3:e000384. https://doi.org/10.1136/rmdopen-2016-000384

    Article  PubMed  PubMed Central  Google Scholar 

  85. Lafyatis R, Kissin E, York M, Farina G, Viger K, Fritzler MJ, Merkel PA, Simms RW (2009) B cell depletion with rituximab in patients with diffuse cutaneous systemic sclerosis. Arthritis Rheum 60:578–583. https://doi.org/10.1002/art.24249

    Article  PubMed  PubMed Central  Google Scholar 

  86. Smith V, Van Praet JT, Vandooren B et al (2010) Rituximab in diffuse cutaneous systemic sclerosis: an open-label clinical and histopathological study. Ann Rheum Dis 69:193–197. https://doi.org/10.1136/ard.2008.095463

    Article  CAS  PubMed  Google Scholar 

  87. Bosello S, De Santis M, Lama G et al (2010) B cell depletion in diffuse progressive systemic sclerosis: safety, skin score modification and IL-6 modulation in an up to thirty-six months follow-up open-label trial. Arthritis Res Ther 12:R54. https://doi.org/10.1186/ar2965

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  88. Thiebaut M, Launay D, Rivière S, Mahévas T, Bellakhal S, Hachulla E, Fain O, Mekinian A (2018) Efficacy and safety of rituximab in systemic sclerosis: French retrospective study and literature review. Autoimmun Rev 17:582–587. https://doi.org/10.1016/j.autrev.2017.12.010

    Article  CAS  PubMed  Google Scholar 

  89. Melsens K, Vandecasteele E, Deschepper E, Badot V, Blockmans D, Brusselle G, de Langhe E, de Pauw M, Debusschere C, Decuman S, Deroo L, Houssiau F, Lenaerts J, Piette Y, Thevissen K, Vanthuyne M, Westhovens R, Wijnant S, de Keyser F, Smith V (2018) Two years follow-up of an open-label pilot study of treatment with rituximab in patients with early diffuse cutaneous systemic sclerosis. Acta Clin Belg 73:119–125. https://doi.org/10.1080/17843286.2017.1372244

    Article  PubMed  Google Scholar 

  90. Narváez J, LLuch J, Molina-Molina M et al (2020) Rituximab as a rescue treatment added on mycophenolate mofetil background therapy in progressive systemic sclerosis associated interstitial lung disease unresponsive to conventional immunosuppression. Semin Arthritis Rheum 50:977–987. https://doi.org/10.1016/j.semarthrit.2020.08.004

    Article  CAS  PubMed  Google Scholar 

  91. Daoussis D, Liossis S-NC, Tsamandas AC et al (2012) Effect of long-term treatment with rituximab on pulmonary function and skin fibrosis in patients with diffuse systemic sclerosis. Clin Exp Rheumatol 30:S17–S22

    PubMed  Google Scholar 

  92. Daoussis D, Melissaropoulos K, Sakellaropoulos G, Antonopoulos I, Markatseli TE, Simopoulou T, Georgiou P, Andonopoulos AP, Drosos AA, Sakkas L, Liossis SN (2017) A multicenter, open-label, comparative study of B-cell depletion therapy with rituximab for systemic sclerosis-associated interstitial lung disease. Semin Arthritis Rheum 46:625–631. https://doi.org/10.1016/j.semarthrit.2016.10.003

    Article  CAS  PubMed  Google Scholar 

  93. Bosello SL, De Luca G, Rucco M et al (2015) Long-term efficacy of B cell depletion therapy on lung and skin involvement in diffuse systemic sclerosis. Semin Arthritis Rheum 44:428–436. https://doi.org/10.1016/j.semarthrit.2014.09.002

    Article  PubMed  Google Scholar 

  94. Jordan S, Distler JHW, Maurer B, Huscher D, van Laar J, Allanore Y, Distler O, EUSTAR Rituximab study group (2015) Effects and safety of rituximab in systemic sclerosis: an analysis from the European Scleroderma Trial and Research (EUSTAR) group. Ann Rheum Dis 74:1188–1194. https://doi.org/10.1136/annrheumdis-2013-204522

    Article  CAS  PubMed  Google Scholar 

  95. Elhai M, Boubaya M, Distler O, Smith V, Matucci-Cerinic M, Alegre Sancho JJ, Truchetet ME, Braun-Moscovici Y, Iannone F, Novikov PI, Lescoat A, Siegert E, Castellví I, Airó P, Vettori S, de Langhe E, Hachulla E, Erler A, Ananieva L, Krusche M, López-Longo FJ, Distler JHW, Hunzelmann N, Hoffmann-Vold AM, Riccieri V, Hsu VM, Pozzi MR, Ancuta C, Rosato E, Mihai C, Kuwana M, Saketkoo LA, Chizzolini C, Hesselstrand R, Ullman S, Yavuz S, Rednic S, Caimmi C, Bloch-Queyrat C, Allanore Y, for EUSTAR network (2019) Outcomes of patients with systemic sclerosis treated with rituximab in contemporary practice: a prospective cohort study. Ann Rheum Dis 78:979–987. https://doi.org/10.1136/annrheumdis-2018-214816

    Article  CAS  PubMed  Google Scholar 

  96. Goswami RP, Ray A, Chatterjee M et al (2020) Rituximab in the treatment of systemic sclerosis–related interstitial lung disease: a systematic review and meta-analysis. Rheumatology. https://doi.org/10.1093/rheumatology/keaa550

  97. Tang R, Yu J, Shi Y, Zou P, Zeng Z, Tang B, Wang Y, Ling G, Luo M, Xiao R (2020) Safety and efficacy of rituximab in systemic sclerosis: a systematic review and meta-analysis. Int Immunopharmacol 83:106389. https://doi.org/10.1016/j.intimp.2020.106389

    Article  CAS  PubMed  Google Scholar 

  98. Hughes M, Denton CP, Khanna D (2020) Rituximab for the treatment of systemic sclerosis-interstitial lung disease. Rheumatology. https://doi.org/10.1093/rheumatology/keaa675

  99. Gordon JK, Martyanov V, Franks JM, Bernstein EJ, Szymonifka J, Magro C, Wildman HF, Wood TA, Whitfield ML, Spiera RF (2018) Belimumab for the treatment of early diffuse systemic sclerosis: results of a randomized, double-blind, placebo-controlled, pilot trial. Arthritis Rheum 70:308–316. https://doi.org/10.1002/art.40358

    Article  CAS  Google Scholar 

  100. Schiopu E, Chatterjee S, Hsu V, Flor A, Cimbora D, Patra K, Yao W, Li J, Streicher K, McKeever K, White B, Katz E, Drappa J, Sweeny S, Herbst R (2016) Safety and tolerability of an anti-CD19 monoclonal antibody, MEDI-551, in subjects with systemic sclerosis: a phase I, randomized, placebo-controlled, escalating single-dose study. Arthritis Res Ther 18:1–14. https://doi.org/10.1186/S13075-016-1021-2

    Article  Google Scholar 

  101. Streicher K, Sridhar S, Kuziora M, Morehouse CA, Higgs BW, Sebastian Y, Groves CJ, Pilataxi F, Brohawn PZ, Herbst R, Ranade K (2018) Baseline plasma cell gene signature predicts improvement in systemic sclerosis skin scores following treatment with inebilizumab (MEDI-551) and correlates with disease activity in systemic lupus erythematosus and chronic obstructive pulmonary disease. Arthritis Rheum 70:2087–2095. https://doi.org/10.1002/art.40656

    Article  CAS  Google Scholar 

  102. Daoussis D, Liossis S-N (2019) Treatment of systemic sclerosis associated fibrotic manifestations: current options and future directions. Mediterr J Rheumatol 30:33–37. https://doi.org/10.31138/mjr.30.1.33

    Article  PubMed  PubMed Central  Google Scholar 

  103. Dimitroulas T, Daoussis D, Garyfallos A, Sfikakis P, Kitas G (2015) Molecular and cellular pathways as treatment targets for biologic therapies in systemic sclerosis. Curr Med Chem 22:1943–1955. https://doi.org/10.2174/0929867322666150209161224

    Article  CAS  PubMed  Google Scholar 

  104. Melissaropoulos K, Kraniotis P, Bogdanos D, Dimitroulas T, Sakkas L, Daoussis D (2019) Targeting very early systemic sclerosis: a case-based review. Rheumatol Int 39:1961–1970. https://doi.org/10.1007/s00296-019-04357-x

    Article  PubMed  Google Scholar 

  105. Antonopoulos I, Daoussis D, Lalioti M-E, Markatseli TE, Drosos AA, Taraviras S, Andonopoulos AP, Liossis SNC (2019) B cell depletion treatment decreases CD4+IL4+ and CD4+CD40L+ T cells in patients with systemic sclerosis. Rheumatol Int 39:1889–1898. https://doi.org/10.1007/s00296-019-04350-4

    Article  CAS  PubMed  Google Scholar 

  106. Daoussis D, Tsamandas A, Antonopoulos I, Filippopoulou A, Papachristou DJ, Papachristou NI, Andonopoulos AP, Liossis SN (2016) B cell depletion therapy upregulates Dkk-1 skin expression in patients with systemic sclerosis: association with enhanced resolution of skin fibrosis. Arthritis Res Ther 18:118. https://doi.org/10.1186/s13075-016-1017-y

    Article  CAS  PubMed  PubMed Central  Google Scholar 

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  1. Department of Rheumatology, Agios Andreas Hospital, Patras, Greece

    Konstantinos Melissaropoulos

  2. Department of Internal Medicine, Division of Rheumatology, Patras University Hospital, University of Patras Medical School, 26504 Rion, Patras, Greece

    Dimitrios Daoussis

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Melissaropoulos, K., Daoussis, D. B cells in systemic sclerosis: from pathophysiology to treatment. Clin Rheumatol 40, 2621–2631 (2021). https://doi.org/10.1007/s10067-021-05665-z

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